Adipose stromal cells (ASCs) are the major source for some adipose tissue-derived, tumor-promoting factors including estrogens and various cytokines. Emerging evidence indicates that circulating ASCs are distinctly associated with obese individuals, in particular obese cancer patients. Functionally, circulating ASCs can travel to tumor stroma in distant organs to promote tumor progression. However, as circulating ASCs are relatively rare, they are unlikely to outnumber resident ASCs that are often abundantly present in tumor stroma. Are circulating ASCs different from resident ASCs that have never been exposed to circulation? Does the blood journey per se endow certain enduring features to circulating ASCs, which in turn enhances their tumor-promoting activity? High compliance or low rigidity is a salient mechanical property that sets liquid tissue apart from solid tissue. Correspondingly, cells adopt different sizes and shapes in these two mechanically different matrices. Our preliminary work indicates that a compliant matrix and/or a round cell shape, both of which are reminiscent of the mechanical phenotype in blood, substantially stimulate estrogen production in ASCs and in turn the ability of these stromal cells to promote proliferation of estrogen receptor ? (ER)-positive breast cancer cells. In the current proposal, we will test the hypothesis that the mechanically compliant environment in blood induces transcriptional and epigenetic reprogramming of circulating ASCs. This process may result in elevated endocrine output and tumor-promoting activity of circulating ASCs, thus enabling them to outperform resident ASCs at a distant tumor-containing solid tissue. We will combine complementary systems (cell culture, animal models, and clinical samples), cross-disciplinary expertise (bioengineering, adipose/cancer biology, and epigenetics), and cutting-edge technologies (single-cell isolation and analysis) to test this novel hypothesis. Fat-laden adipocyte has been the primary focus in studies of obesity-related cancer risk. By exploring a link between mechanical compliance, epigenetic reprogramming, and endocrine output of circulating ASCs, the proposed work integrates historically separate areas of research and promises to offer new insights into an under-investigated, obesity-associated cell population. In addition, the novel concept of mechanically induced reprogramming may have a far-reaching impact on studies of other circulating cell types that are involved in cancer progression and metastasis.